Epstein-Barr virus (EBV) is a member of the herpes virus family, causing infectious mononucleosis and establishing life-long latency in infected individuals. EBV is also associated with cancers of both B cells and epithelial cells, the two cell types that it infects in vivo. EBV entry into B cells and epithelial cells requires the coordinated action of four (gH, gL, gB and gp42) and three (gH, gL and gB) viral glycoproteins, respectively. The process by which receptor recognition triggers membrane fusion and virus entry is not well understood. The gH, gL and gB proteins form the core fusion machinery for all herpesviruses and it is thought that gB acts as the primary fusogen in this process. The gH/gL heterodimer is thought to act as the regulator for gB activation, triggering conformational changes in gB after receptor binding. We recently determined the low- resolution electron microscopy structure of the EBV B cell entry triggering complex composed of gH/gL, gp42 and host receptor HLA, clarifying how this complex bridges the viral and cellular membranes, bringing them into closer proximity prior to gB activation. Here, we (the Jardetzky, Longnecker and Zhou research groups) propose to study complexes of wild type and mutant gH/gL with integrins that act as the entry receptor for EBV infection of epithelial cells by a combination of virology, mutagenesis and biophysics means. We will first characterize molecular interactions between the wt (wild type) or mutant gH/gL proteins and integrin receptors and determine how initial complexes between gH/gL and integrins may convert to an activated state to trigger gB- mediated fusion. We will then compare the architectures of the B cell and epithelial cell triggering complexes by cryo electron microscopy. The anticipated results would establish the molecular interactions of the two EBV entry complexes and reveal the structural commonalities between them. Such structural information is key to understanding the subsequent steps of gB activation and EBV entry and, by extension, the general mechanism of cell entry by human herpesviruses.